5-chloro-3-(4-methanesulfonylphenyl)-6&#39;-methyl-[2,3]bipyridinyl in pure crystalline form and process for synthesis

ABSTRACT

This invention encompasses a pharmaceutical composition comprising the compound of formula A:  
                 
 
     in combination with a pharmaceutically acceptable carrier, said compound being comprised of about 1-50%, 1-20% or 1-10% of the polymorphic form which is designated Form V and the remainder of the compound being comprised of at least one polymorphic form selected from the group consisting of: Form I, Form II, Form III and Form IV

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. ApplicationNo. 09/865,771, filed May 25, 2001, which claims the benefit of U.S.Provisional Application No. 60/208,017, filed May 26, 2000.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to the Form V polymorph of CompoundA having the chemical structure shown below:

[0003] as well as a process for synthesizing the Form V polymorph.

[0004] Compound A exists in five polymorphic forms (Forms I-V), anamorphous form and two hydrated forms. The compound is a potent andselective cyclooxygenase-2 (COX-2) inhibitor, useful primarily in thetreatment of inflammation, pain and fever as well as other COX-2mediated diseases, such as described in PCT Publication Nos. WO96/10012and WO96/16934. Compound A is described in U.S. Pat. No. 5,861,419granted on Jan. 19, 1999 (Example 23), which is hereby incorporated byreference in its entirety. A process for making Compound A is describedin U.S. Pat. No. 6,040,319 granted on Mar. 21, 2000, which is herebyincorporated by reference in its entirety. The present inventionunexpectedly provides for a novel, robust process for making a Form Vpolymorph of compound A from any one of Forms I, II, III or IV or anymixture of polymorphs of compound A.

SUMMARY OF THE INVENTION

[0005] This invention encompasses the Form V polymorph of structuralformula A:

[0006] which is useful in the treatment of cyclooxygenase-2 mediateddiseases.

[0007] The invention encompasses certain pharmaceutical compositions forthe treatment of cyclooxygenase-2 mediated diseases comprising the FormV polymorph of Compound A. The invention also encompasses a process forsynthesizing the Form V polymorph of Compound A comprising: combiningpolymorph I, II, III or IV of Compound A with isopropyl acetate; heatingto an elevated temperature less than about 75° C.; and cooling to a lowtemperature to produce the Form V polymorph.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The invention is described in connection with the appendeddrawings in which:

[0009]FIG. 1 is the X-ray powder diffraction (XRPD) pattern of Form V;

[0010]FIG. 2 is the XRPD pattern of Form I;

[0011]FIG. 3 is the XRPD pattern of Form II;

[0012]FIG. 4 is the XRPD pattern of Form III;

[0013]FIG. 5 is the XRPD pattern of Form IV;

[0014]FIG. 6 is the XRPD pattern of the hemihydrate; and

[0015]FIG. 7 is the XRPD pattern of the sesquihydrate.

DETAILED DESCRIPTION

[0016] This invention encompasses the Form V polymorph of structuralformula A:

[0017] having the following physical characteristics: DSC extrapolatedonset melting temperature of 133.9° C., DSC peak melting temperature of134.5° C., and x-ray powder diffraction peak positions, Cu K alpha, of:13.7, 7.2, 6.9, 6.7, 5.8, 5.7, 5.0, 4.9, 4.8, 4.7, 4.5, 4.2, 4.0, 3.9,3.8, 3.7, 3.6, 3.4, 3.3, 3.1, 3.0, 2.9 and 2.8 angstroms.

[0018] An embodiment of the invention is the Form V polymorph ofCompound A characterized as having an x-ray powder diffraction patternpeak position, Cu K alpha, at about 13.7 angstroms. Within thisembodiment of the invention is the Form V polymorph of Compound Afurther characterized as having at least one x-ray powder diffractionpattern peak position, Cu K alpha, at about: 7.2, 6.9, 6.7, 5.8, 5.7,5.0, 4.9, 4.8, 4.7, 4.5, 4.2, 4.0, 3.9, 3.8, 3.7, 3.6, 3.4, 3.3, 3.1,3.0, 2.9 or 2.8 angstroms.

[0019] An embodiment of the invention is the Form V polymorph ofCompound A characterized as having a DSC extrapolated onset meltingtemperature of about 133.9° C.

[0020] An embodiment of the invention is the Form V polymorph ofCompound A characterized as having a DSC peak melting temperature ofabout 134.5° C.

[0021] An embodiment of the invention is the Form V polymorph ofCompound A having the aforesaid characteristics in substantially pureform.

[0022] The invention also encompasses a pharmaceutical compositioncomprising a non-toxic therapeutically effective amount of a Form Vpolymorph of Compound A and a pharmaceutically acceptable carrier.

[0023] An embodiment of the invention encompasses a method of treatingan inflammatory disease susceptible to treatment with an non-steroidalanti-inflammatory agent comprising administering to a patient in need ofsuch treatment a non-toxic therapeutically effective amount of a Form Vpolymorph of Compound A.

[0024] Another embodiment of the invention encompasses a method oftreating a cyclooxygenase mediated disease advantageously treated by anactive agent that selectively inhibits cyclooxygenase-2 in preference tocyclooxygenase-1 comprising administering to a patient in need of suchtreatment a non-toxic therapeutically effective amount of a Form Vpolymorph of Compound A.

[0025] Another embodiment of the invention encompasses a method fortreating an illness selected from the group consisting of: (a) rheumaticfever, (b) symptoms associated with influenza or other viral infections,common cold, (c) low back and neck pain, (d) dysmenorrhea, (e) headache,(f) toothache, (g) sprains and strains, (h) myositis, (i) neuralgia, (j)synovitis, (k) arthritis, including rheumatoid arthritis, degenerativejoint diseases (osteoarthritis), gout and ankylosing spondylitis, (l)bursitis, (m) bums, (n) injuries, and (o) following surgical and dentalprocedures, comprising administering to a patient in need of suchtreatment a non-toxic therapeutically effective amount of a Form Vpolymorph of Compound A.

[0026] This invention also encompasses a novel process for making a FormV polymorph of structural formula A comprising: combining polymorph I,II, III or IV of Compound A with isopropyl acetate; heating to anelevated temperature less than about 75° C.; and cooling to a lowtemperature to produce the Form V polymorph.

[0027] For purposes of this Specification, the term ‘elevatedtemperature’ means any temperature above room temperature but less thanabout 75° C., as high as about 35-70° C., preferably about 50-65° C.Room temperature is about 20° C. The term ‘low temperature’ means anytemperature below the ‘elevated temperature’, as low as about 0-30° C.,preferably as low as about 10-20° C.

[0028] Polymorphic forms of Compound A, for purposes of this invention,are identified as Form I (onset of melting m.p. 135.7±0.2° C., peak m.p.137.0±0.2° C.), Form II (onset of melting m.p 129.6° C., peak m.p.131.5° C.), Form III (onset of melting m.p. 133.2° C., peak m.p. 134.4°C.), Form IV (onset of melting m.p. 133.72±0.04° C., peak m.p.134.5±0.1° C.) and Form V (onset of melting, m.p. 133.9° C., peak m.p.134.5° C.). Forms I through V are anhydrous.

[0029] An embodiment of the invention encompasses the process for makingthe Form V polymorph of Compound A which further comprises isolating theForm V polymorph. A subset of this embodiment encompasses isolating theForm V polymorph by filtration.

[0030] An embodiment of the invention is the process for making a Form Vpolymorph of Compound A wherein the elevated temperature is about 40-75°C. Another embodiment of the invention is the process for making a FormV polymorph of Compound A wherein the elevated temperature is about50-65° C.

[0031] An embodiment of the invention is the process for making a Form Vpolymorph of Compound A wherein the low temperature is about 0-30° C.Another embodiment of the invention is the process for making a Form Vpolymorph of Compound A wherein the low temperature is about 10-20° C.

[0032] Another embodiment of the invention is the process for making aForm V polymorph of Compound A wherein the elevated temperature is about50-65° C. and the low temperature is about 10-20° C.

[0033] The invention will now be illustrated by the followingnon-limiting examples:

Preparative Example A

[0034] The starting material Compound A was made in accordance with U.S.Pat. No. 6,040,319.

Preparative Example B Form II

[0035] Form II was obtained by crystallizing Compound A obtained inaccordance with Preparative Example A from ethyl acetate. DifferentialScanning Calorimetry showed an extrapolated onset of melting at about130° C., and a peak melting point of about 131° C.

Preparative Example C Form IV

[0036] Form IV was prepared by mixing Preparative Example A (550.0g,1.54 mol) and toluene (4.0 L) and heating the mixture to 32.6° C. tocause dissolution. The solution was cooled to 16.5° C. and Form IVcrystallized. The mixture was then cooled to 0° C. over 1 hr. n-Heptane(7.0 L) was added over 2 hr and the mixture was filtered. The cake waswashed with 3:1 n-heptane/toluene (3.0 L) and dried to give the product(521.0 g) as a granular solid.

Preparative Example D Hemihydrate

[0037] A solution of Preparative Example A (65 g) in 1 L of water wettoluene was heated to 60° C. and then cooled to ambient temperature. Thehemihydrate form crystallized and was isolated by filtration. The solidswere dried at ambient temperature under vacuum to give ˜30 g of acolorless crystals.

Preparative Example E Form III

[0038] The hemihydrate of Preparative Example D was heated to 90° C. ina vacuum oven for 12 hours and cooled down in the vacuum oven to givethe Form III polymorph.

Preparative Example G Amorphous

[0039] The amorphous form of compound A was obtained by heating the FormIV from Preparative Example C to above its melting temperature (aboveabout 135° C.) under nitrogen, followed by quench cooling to roomtemperature under a dry atmosphere.

Preparative Example H Mixture of Polymorphs

[0040] Compound 1 was synthesized in accordance with Preparative Example1 of U.S. Pat. No. 6,040,319. Compound 2 was synthesized in accordancewith Example 1 of U.S. Pat. No. 6,040,319.

[0041] To a slurry of Compound 1 (1.10 kg) in tetrahydrofuran (THF) (2.5L) at 0° C. was added potassium tert-butoxide (2.47 L). The resultingmixture was transferred to a slurry of Compound 2 (1.19 kg) in TUF atambient temperature. The slurry was transferred to a solution of aceticacid (1.5 L) and trifluoroacetic acid (TFA) (0.23 L) in THF.Concentrated ammonium hydroxide (1.50 L) was added and the mixture toreflux. The reaction mixture was cooled and the phases were cut. The THFlayer was concentrated and toluene was added. The toluene layer waswashed with aqueous sodium hydroxide followed by water and thenconcentrated to ˜6 L. Acetone was added and a solution ofp-toluenesulfonic acid (pTSA) (0.73 kg) in acetone was added and batchwas filtered. The filter cake was washed with toluene/acetone and thesolid dried in vacuo to give 1.80 kg of Compound 3 in ˜90% isolatedyield as an off white solid.

[0042] To a mixture of toluene, water and Compound 3 (1.80 kg) was addedaqueous ammonia (1 equiv.). The phases were cut and the toluene layerwas washed with water. The mixture was filtered through SOLKAFLOC andthe filtrate was concentrated to a saturated solution and then cooled toambient temperature and n-heptane was added. The solid was isolated byfiltration, washed with toluene/n-heptane and then dried in vacuo togive Preparative Example H as an off-white solid.

EXAMPLE 1 FORM V OF5-CHLORO-3-(4-METHANESULFONYLPHENYL)-6′-METHYL-[2,3′]BIPYRIDINYL

[0043] A mixture of Preparative Example H and isopropyl acetate (IPAC)was heated at 55° C. The suspension was cooled to ambient temperatureand the solids were isolated by filtration. The solids were washed withIPAC and dried in vacuo to give the Form V polymorph (1.1 kg) as acolorless solid in ˜87% yield.

[0044]¹H NMR (400 MHz CDCl₃) δ8.69 (d, 1H, J=2.3 Hz), 8.36 (3, 1H, J=2.2Hz), 7.88 (d, 2H, J=8.4 Hz), 7.72 (d, 1H, J=2.3 Hz), 7.54 (dd, 1H,J₁=8.0 Hz, J₂=2.3 Hz), 7.38 (d, 2H, J=8.5 Hz), 7.07 (d, 1H, J=8.0 Hz),3.06 (s, 3H), 2.51 (s, 3H); ¹³C NMR (100 MHz CDCl₃) δ158.4, 152.2,149.7, 148.3, 143.7, 140.1, 137.9, 137.2, 135.18. 131.1, 130.0, 130.3,127.8, 122.7, 44.4, 24.1.

Characterization of Polymorphs

[0045] The polymorphic forms of compound A were characterized using thefollowing procedures.

X-Ray Powder Diffraction Pattern Analysis

[0046] The X-ray patterns were collected using a Philips APD powderdiffractometer utilizing copper K-alpha radiations. Table 1 below liststhe XRPD peak locations for Forms I, II, III, IV and V as well as thehemihydrate and sesquihydrate forms. The peak positions are expressed inangstroms in Table 1. TABLE 1 X-ray Powder Diffraction D-spacing forCrystalline Phases in Reflections (angstroms) Hemi- Sesqui- Form I FormII Form III Form IV Form V hydrate hydrate 12.6 16.1 10.8 10.4 13.7 10.912.7 9.1 9.4 8.2 5.9 7.2 10.6 10.2 7.5 8.3 6.9 5.4 6.9 6.2 8.0 7.2 6.86.4 5.2 6.7 5.8 7.7 6.8 5.3 6.2 5.0 5.8 5.6 7.5 5.7 5.2 5.7 4.7 5.7 5.56.3 5.4 5.1 5.4 4.6 5.0 5.3 6.0 4.9 4.8 5.0 4.1 4.9 5.0 5.8 4.6 4.5 4.64.0 4.8 4.6 5.4 4.4 4.3 4.5 3.9 4.7 4.4 5.1 4.2 4.1 4.1 3.8 4.5 4.2 4.84.1 3.9 3.9 3.6 4.2 4.1 4.5 3.9 3.8 3.8 3.3 4.0 4.0 4.2 3.8 3.6 3.7 3.13.9 3.8 4.1 3.7 3.5 3.5 3.0 3.8 3.6 4.0 3.4 3.4 3.3 3.7 3.4 3.9 3.1 3.23.2 3.6 3.2 3.7 3.0 3.1 3.4 3.1 3.5 2.8 3.3 3.4 3.1 3.3 3.0 3.1 2.9 2.8

[0047] The XPRD pattern for Form V is shown in FIG. 1. XRPD patterns forForms I-IV are shown in FIGS. 2-5. XRPD patterns for the two hydrateforms are shown in FIGS. 6 and 7. The peak positions are expressed indegrees (2 theta) in the plots.

Differential Scanning Calorimetry (DSC)

[0048] DSC was carried out using a TA Instruments DSC 2910 instrument ata heating rate of 1° C./min under a nitrogen atmosphere in an open pan.The extrapolated onset temperatures, T_(O), and enthalpy of fusion, ΔH,observed for the melting endotherms are shown in Table 2 for Forms I,II, III, IV and V. TABLE 2 Extrapolated melting temperature onset,T_(O), and Enthalpy of Fusion obtained by DSC at 1° C./min in an openpan under nitrogen Polymorphic form T_(O) (° C.) Enthalpy of fusion, J/gForm I 135.7 ± 0.2 72.9 ± 2.0 Form II 129.6 Form III 133.2 Form IV133.72 ± 0.04 76.9 ± 1.4 Form V 133.9 84.8

[0049] Another embodiment of the invention encompasses a pharmaceuticalcomposition comprising the compound of formula A:

[0050] in combination with a pharmaceutically acceptable carrier, saidcompound of formula A being comprised of about 1-50% of the polymorphicform which is designated Form V and the remainder of the compound beingcomprised of at least one polymorphic form selected from the groupconsisting of: Form I, Form II, Form III and Form IV.

[0051] Another embodiment of the invention encompasses a pharmaceuticalcomposition comprising the compound of formula A in combination with apharmaceutically acceptable carrier, said compound of formula A beingcomprised of about 1-20% of the polymorphic form which is designatedForm V and the remainder of the compound being comprised of at least onepolymorphic form selected from the group consisting of: Form I, Form II,Form III and Form IV.

[0052] Another embodiment of the invention encompasses a pharmaceuticalcomposition comprising the compound of formula A in combination with apharmaceutically acceptable carrier, said compound of formula A beingcomprised of about 1-10% of the polymorphic form which is designatedForm V and the remainder of the compound being comprised of at least onepolymorphic form selected from the group consisting of: Form I, Form II,Form III and Form IV.

[0053] Within this embodiment is encompassed the pharmaceuticalcompositions described above wherein the polymorphic form designatedForm V is characterized as having an x-ray powder diffraction patternpeak position, Cu K alpha, at about 13.7 angstroms.

[0054] Also, within this embodiment is encompassed the pharmaceuticalcompositions described above wherein the polymorphic form designatedForm V is characterized as having at least one x-ray powder diffractionpattern peak position, Cu K alpha, at about: 7.2, 6.9, 6.7, 5.8, 5.7,5.0, 4.9, 4.8, 4.7, 4.5, 4.2, 4.0, 3.9, 3.8, 3.7, 3.6, 3.4, 3.3, 3.1,3.0, 2.9 or 2.8 angstroms.

[0055] Also, within this embodiment is encompassed the pharmaceuticalcompositions described above wherein the polymorphic form designatedForm V is characterized as having a DSC extrapolated onset meltingtemperature of about 133.9° C.

[0056] Also within this embodiment is encompassed the pharmaceuticalcompositions described above wherein the polymorphic form designatedForm V is characterized as having a DSC peak melting temperature ofabout 134.5° C.

[0057] The invention also encompasses a method of treating aninflammatory disease susceptible to treatment with an non-steroidalanti-inflammatory agent comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of the pharmaceuticalcompositions described above.

[0058] The invention also encompasses a method of treating acyclooxygenase mediated disease advantageously treated by an activeagent that selectively inhibits cyclooxygenase-2 in preference tocyclooxygenase-1 comprising administering to a patient in need of suchtreatment a therapeutically effective amount of the pharmaceuticalcompositions described above.

[0059] The invention also encompasses a method for treating an illnessselected from the group consisting of: (a) rheumatic fever, (b) symptomsassociated with influenza or other viral infections, common cold, (c)low back and neck pain, (d) dysmenorrhea, (e) headache, (f) toothache,(g) sprains and strains, (h) myositis, (i) neuralgia, (j) synovitis, (k)arthritis, including rheumatoid arthritis, degenerative joint diseases(osteoarthritis), gout and ankylosing spondylitis, (l) bursitis, (m)bums, (n) injuries, and (o) following surgical and dental procedures,comprising administering to a patient in need of such treatment atherapeutically effective amount of the pharmaceutical compositionsdescribed above.

[0060] Polymorphic forms I, II, III and IV as well as the hemihydrate,sesquihydrate and amorphous forms of the compound of Formula A aredescribed in WO/0137833 published on May 31, 2001, which is herebyincorporated by reference in its entirety.

What is claimed is:
 1. A pharmaceutical composition comprising thecompound of formula A:

in combination with a pharmaceutically acceptable carrier, said compoundof formula A being comprised of about 1-50% of the polymorphic formwhich is designated Form V and the remainder of the compound beingcomprised of at least one polymorphic form selected from the groupconsisting of: Form I, Form II, Form III and Form IV.
 2. Thepharmaceutical composition according to claim 1 wherein: said compoundof formula A is comprised of about 1-20% of the polymorphic form whichis designated Form V and the remainder of the compound being comprisedof at least one polymorphic form selected from the group consisting of:Form I, Form II, Form III and Form IV.
 3. The pharmaceutical compositionaccording to claim 2 wherein: said compound of formula A is comprised ofabout 1-10% of the polymorphic form which is designated Form V and theremainder of the compound being comprised of at least one polymorphicform selected from the group consisting of: Form I, Form II, Form IIIand Form IV.
 4. The pharmaceutical composition according to claim 1wherein the polymorphic form designated Form V is characterized ashaving an x-ray powder diffraction pattern peak position, Cu K alpha, atabout 13.7 angstroms.
 5. The pharmaceutical composition according toclaim 1 wherein the polymorphic form designated Form V is characterizedas having at least one x-ray powder diffraction pattern peak position,Cu K alpha, at about: 7.2, 6.9, 6.7, 5.8, 5.7, 5.0, 4.9, 4.8, 4.7, 4.5,4.2, 4.0, 3.9, 3.8, 3.7, 3.6, 3.4, 3.3, 3.1, 3.0, 2.9 or 2.8 angstroms.6. The pharmaceutical composition according to claim 1 wherein thepolymorphic form designated Form V is characterized as having a DSCextrapolated onset melting temperature of about 133.9° C.
 7. Thepharmaceutical composition according to claim 1 wherein the polymorphicform designated Form V is characterized as having a DSC peak meltingtemperature of about 134.5° C.
 8. A method of treating an inflammatorydisease susceptible to treatment with an non-steroidal anti-inflammatoryagent comprising administering to a patient in need of such treatment atherapeutically effective amount of the pharmaceutical compositionaccording to claim
 1. 9. A method of treating a cyclooxygenase mediateddisease advantageously treated by an active agent that selectivelyinhibits cyclooxygenase-2 in preference to cyclooxygenase-1 comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of the pharmaceutical composition according to claim 1.